Patients with resectable stage III melanoma who have a major pathologic response (MPR) to neoadjuvant therapy can skip therapeutic lymph node dissection (TLND) and adjuvant therapy — with their associated morbidity and toxicity — and still achieve high 2-year rates of relapse-free survival (RFS) and distant metastasis-free survival (DMFS), according to research presented at the 2022 ASCO Annual Meeting.
Investigators reported findings from PRADO, an extension cohort of the phase 2 OpACIN-neo study (ClinicalTrials.gov Identifier: NCT02977052) that is seeking to confirm the pathologic response rate (pRR) and safety of neoadjuvant ipilimumab 1 mg/kg plus nivolumab 3 mg/kg and to test response-driven subsequent therapy.
Eligible patients were aged 18 years and older with confirmed resectable stage III melanoma and at least 1 macroscopic lymph node metastasis, and a World Health Organization Performance Status of 0 or 1.
After marker placement in the index lymph node, the patients received 2 cycles of neoadjuvant ipilimumab and nivolumab, with resection of that node scheduled for week 6. Patients who achieved MPR (10% or less viable tumor) in the node did not undergo TLND or receive adjuvant therapy. Patients who had a pathologic partial response (pPR; more than 10% to 50% or less viable tumor) underwent TLND only, and patients having no pathologic response (pNR; more than 50% viable tumor) underwent TLND and received adjuvant therapy for 52 weeks with or without radiotherapy (RT).
The primary endpoints were pRR in the index lymph node and RFS at 2 years.
A total of 99 patients (median age, 58 years; 66% male) were enrolled and treated with at least 1 cycle of neoadjuvant ipilimumab and nivolumab from November 2018 to January 2020. Previous findings demonstrated a pRR of 72% (95% CI, 62%-80%), including 61% of patients with MPR and 11% with pPR. TLND omission in patients with MPR significantly reduced surgical morbidity and improved quality of life. Among the 27 nonresponders, 6 had distant metastasis before index lymph node resection. Of the other 21 patients with pNR, 7 received adjuvant nivolumab, 10 received adjuvant dabrafenib plus trametinib, 3 had no adjuvant therapy, and 1 was lost to follow-up.
The estimated 2-year RFS rate for patients with MPR was 93.3% (95% CI, 87.2%-99.9%) after a median follow-up of 27.9 months, with regional relapse occurring in 4 of 60 participants. The rate of DMFS was 98%. Among the 11 patients with pPR, 4 had relapses, which were distant in all cases, resulting in a 2-year RFS and DMFS rate of 63.6% (95% CI, 40.7%-99.5%).
The 2-year RFS rate in patients with pNR was 71.4% (95% CI, 54.5-93.6), and the DMFS rate was 76.2%. Relapse occurred in 2 of 7 patients with pNR given adjuvant nivolumab and in 3 of 10 patients given adjuvant dabrafenib plus trametinib.
Fatigue (57%) and rash (56%) were the most common any-grade immune-related adverse events. Grade 3 to 4 immune-related adverse events occurred in 30% of patients.
“Patients with pPR seem to have higher relapse rates than suggested previously, and therefore might benefit from additional adjuvant therapy,” stated the investigators. “Addition of adjuvant systemic therapy with or without RT in patients with pNR seems to improve 2-year RFS as compared to historical data.”
Disclosure: This research was supported by Bristol-Myers Squibb. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Blank CU, Reijers ILM, Saw RPM, et al. Survival data of PRADO: A phase 2 study of personalized response-driven surgery and adjuvant therapy after neoadjuvant ipilimumab (IPI) and nivolumab (NIVO) in resectable stage III melanoma. Presented at ASCO 2022; June 3-7, 2022. Abstract 9501.